International collaborative research project to establish reference intervals in harmonisation

The Global Project to Determine Reference Intervals (RIs) in Harmonisation has brought together 19 countries to develop standard methodologies for producing accurate and consistent reference ranges for common clinical tests. This will lead directly to more accurate diagnosis and optimal treatment regimens for patients.

Nearly all decisions regarding the clinical management of patients are made following the results of laboratory tests. However, laboratory tests can only be meaningfully interpreted through reference to a set of normal reference values (RVs) for the parameters being tested. These reference values must reflect the status of a normal healthy individual and encompass the expected variations displayed by people of different weight, ethnicity, gender and other sub-groups. This normal healthy range of variables is called the reference interval (RI) and is a vital tool for clinicians and medical researchers.

The project described in this article has brought together 19 countries, of which 12 have already delivered results that have led to new recommendations. The project was launched in 2012 after two years of discussion on harmonised protocols, followed by a further four years of recruitment, testing and reporting, culminating in papers published in 2017 which recommend standards to be adopted globally for setting RIs.

The issues addressed by the project include: how to exclude values from people with latent diseases; when to separate reference values according to variables such as age and gender; the optimal data size for deriving RVs; and the best statistical means of determining the RI. The research leader explains: 'The objectives were to determine optimal statistical methods based on analyses of real-world datasets from many countries and to explore between-country differences in RVs for the most common laboratory tests. The accumulated data with plenty of information on biological sources of variation will be served as a knowledge base for improved diagnostic use of clinical tests.' The project is a first of its kind. Other than the guidelines issued by the IFCC in the 1990s, there have been few global initiatives tackling this issue, despite the fundamental importance of RIs in clinical decision-making.